Alzheimer's Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative disorders with mid to late life onset such as mixed etiology dementias (MED) including Alzheimer's disease (AD) with TDP-43 pathology. To clarify disease mechanisms and identify therapeutic targets, a new mouse models that replicate combinations of co-occurring pathological features of human dementia will be critical. It is well recognized that AD cases with TDP-43 pathology, as compared to those without, showed a greater decline in cognitive deficits. However, the molecular mechanisms underlying such contribution of TDP-43 remains elusive. We showed that TDP-43 pathology is due to loss of TDP-43's nuclear function, particularly its ability to repress cryptic exon splicing, that precedes formation of TDP-43 cytoplasmic aggregates. That splicing repression is a major role of TDP-43 in forebrain neurons led us to hypothesize that loss of TDP-43 repression exacerbates neurodegeneration and cognitive deficits. To address this question, we will take advantage of 1) our model lacking TDP- 43 in forebrain neurons which exhibits age-dependent neuron loss, cognitive deficits and defects in prelimbic cortical circuits; and 2) our tau model which show, in presence of amyloid plaques, tauopathy- dependent neuron loss, to develop a novel MED model that would exhibit beta-amyloidosis and tauopathy along with compromised TDP-43 repression in forebrain neurons, pathological features that mimic AD with loss of TDP-43 repression. By employing a comprehensive set of molecular, pathological, neuronal circuit and behavioural/cognitive approaches, we will rigorously characterize the MED mice across their lifespan, providing a highly innovative and instructive model to clarify disease mechanism and identify therapeutic targets.